For the most part of the last quarter century, little public or scientific attention focused on issues relating to smallpox or smallpox vaccination but due to current concerns regarding bioterrorism, the potential threat from an outbreak of smallpox through deliberate release has become a real concern. There are several factors that make smallpox a terror weapon of choice. Smallpox can be produced in large quantities, is stable for storage and transportation and can be produced as an aerosol that has a 30% mortality rate in exposed non-vaccinated individuals. It is highly infectious, as 10-20 or more cases can be attributed to have originated from one infected individual. Accordingly, there are great concerns that if a terrorist attack releases smallpox, many U.S. populations will be at risk for infection, disease and death.
The commercially approved smallpox vaccines available for limited use are the established Dryvax vaccine and the Acambis vaccine. This Wyeth vaccine is a lyophilized preparation of live vaccinia virus (VACV) derived from calf lymph. Wyeth discontinued distribution of smallpox vaccine to civilians in 1983. The Acambis vaccine is a live tissue culture adapted vaccine stock that still is associated with severe adverse effects in humans. In the past there were concerns regarding the risks associated with Dryvax. These concerns are heightened by recent adverse events in clinical studies. An important concern is that there are a significant number of immunocompromised (HIV-infected individuals) and a much larger elderly population than was present in 1970. Furthermore pregnant women, intravenous drug users, transplant recipients, and individuals on immunosuppressive drugs living in North America are potential vaccine recipients and are all at increased risk from the original Dryvax or recent Acambis live vaccine strategies. In North America, a concern that an unacceptable number of people may be hospitalized due to serious complications is of major significance. Many people could die from the vaccine alone or, in the case of a bioterror attack using smallpox, there may be slow deployment or non-compliance due to vaccine-related health concerns. Although the recent smallpox vaccination programs are intended to protect against bioterror events, naturally occurring poxvirus diseases are also a growing concern because the number of persons with VACV-induced immunity has been in decline.
Cidofovir, a licensed drug for the treatment of cytomegalovirus retinitis in AIDS patients has broad-spectrum activity against virtually all DNA viruses. Recently, cidofovir demonstrated in vitro and in vivo activity in mice against a number of poxviruses including variola and monkeypox (MPXV). A single dose of cidofovir showed high efficacy in protecting mice from lethal respiratory infection with either vaccinia or cowpox, provided drug treatment is initiated within a few days after exposure.
Still, the current therapies have their limitations. The use of currently stockpiled vaccines to manage a significantly higher rate of complications than occurred in the 1960s is likely not effective, as demands may not be met and efficacy can be reduced due to the evolution of the small pox virus in recent times. There are also the aforementioned safety concerns with individuals that are immunocompromised or have weakened health. The viability of DNA based vaccines is thought to be a potential platform for vaccines, but yet to be proven successful on humans. And further, because smallpox virus is a highly complex DNA virus that encodes over 200 genes and has two infectious forms, the mature virion (MV) and the enveloped virion (EV) each with its own unique set of membrane glycoproteins and different requirements for entry, candidate antigens for developing an effective DNA vaccine has been difficult.
There still remains a need for a safe and effective alternative for current smallpox vaccines. Further, there is a need for a smallpox vaccine that is well tolerated and provides broad immunoprotection, and can be manufactured in large scale in a timely manner in response to bioterror threats.